Bio-flavonoids comprise a group of phenolic secondary plant metabolites that are widespread in nature. Major flavonoids that have well categorized structures and well defined structure function-relationships are: flavans, flavanones, flavones, flavonols, flavanols, flavanonols, cetechins, anthocyanidins and isoflavones. Bio-flavonoids are well-known for their multi-directional biological activities including anti-diabetic efficacy [29-32]. Numerous studies have been carried out to explore their potential role in the treatment of diabetes [27,28,33]. A good number of studies have already demonstrated the
hypoglycemic effects of flavonoids using different experimental models and treatments - the drug candidates have been shown to exert such beneficial effects against the disease manifestation, either through their capacity to avoid glucose
absorption or to improve glucose tolerance. It has also been demonstrated that flavonoids can act per se as insulin secretagogues or insulin mimetics,
probably by influencing the pleiotropic mechanisms, to attenuate the diabetic complications; besides, the drug candidates have been found to stimulate glucose uptake in peripheral tissues, and regulate the activity and/or expression of the rate-limiting enzymes involved in carbohydrate metabolism pathway. As a result, bio-flavonoids are now-a-days regarded as promising and significantly attractive natural substances to enrich the current therapy options against diabetes. This present section embodies the information on promising anti-diabetic efficacies of certain bio-flavonoids.
Choi et al. [34] demonstrated that intraperitoneal administration of prunin (naringenin 7-O-β-D-glucoside) produces a significant hypoglycemic effect in diabetic rats. Anti-hyperglycemic effects have also been demonstrated for various flavonoids including chrysin and its derivatives, silymarin, isoquercetrin and rutin [35-37]. Long-term studies carried out with rutin orally administered to diabetic rats showed that it decreased the plasma glucose levels by up to 60% when compared to the control group. However, oral administration of rutin to normal rats did not show any significant effect on fasting plasma glucose levels [38]. Chronic treatment with hesperidin and naringin was found to lower the blood glucose level of db/db mice compared with the control group [39].
Myrciacitrins I, II, III, IV and V (1-5) isolated from the dried leaves of Myrcia multiflora DC. (family: Myrtaceae) were reported to possess significant rat lens aldose reductase inhibitory activity [40], the IC50 values for the flavonoids 1-5 were determined as 3.2 x 10−6, 1.5 x 10−5, 4.6 x 10−5, 7.9 x 10−7, 1.6 x 10−5 and 1.3 x 10−5 M, respectively [40,41]. Hence, myrciacitrin IV (4) exhibited the most potent activity, although it had less activity than epalrestat, a commercially available synthetic aldose reductase inhibitor (IC50 = 7.2 x 10−8 M) [40].
Kawabata et al. [42] isolated five 6-hydroxy-flavonoids (6-10) from the methanol extract of Origanum majorana L. (family: Lamiaceae) leaves and studied their α-glucosidase enzyme inhibitory activity, three of these flavonoids: 6-hydroxyapigenin (scutellarein) (6), 6-hydroxyapigenin-7-O-β
-D-glucopyranoside (7), 6-hydroxyluteolin-7-O-β-D-glucopyranoside (8) are previously known [43-47], and the other two feruloylglucosides namely,
6-hydroxyapigenin-7-O-(6-O-feruloyl)-β-D-glucopyranoside (9) and 6-hydroxyluteolin-7-O-(6-O-feruloyl)-β-D-glucopyranoside (10) are novel compounds. All the isolates showed rat intestinal α-glucosidase inhibitory activity, at an equal concentration of 500 μM, the flavonoid candidates 6-10
inhibited the enzyme activity by 81%, 44%, 55%, 25% and 26%, respectively.
The respective IC50 values for 6-10 were determined as 12, >500, 300,
>500 and >500 μM. Another flavonoid, 6-hydroxyluteolin (11) [48], was also found to exhibit potent α-glucosidase inhibitory activity (92% inhibition at a concentration of 500 μM) with an IC50 value of 10 μM [42]. The same group [49] also evaluated 5,6,7-trihydroxyflavone (baicalein, 12), the flanonoid constituent of Scutellaria baicalensis, as an important inhibitor against rat intestinal α-glucosidase (IC50 = 32 μM).
The investigators also observed that apigenin (5,7,4′-trihydroxyflavone,
13) and luteolin (5,7,3′,4′-tetrahydroxyflavone, 14), both lacking the 6-hydroxyl substituent, showed negligible activity (12% and 22% inhibition at
500 μM, respectively) in the α-glucosidase inhibitory assay. From their study, the present investigators suggested that 5,6,7-trihydroxyflavone skeleton is crucial for high α-glucosidase inhibitory activity regardless of B-ring hydroxylation, in addition, glycosation of 7-hydroxyl substituent as well as acylation of the sugar reduces the enzyme inhibitory activity [49].
Haraguchi et al. [50] isolated C-glucosidic flavone derivative named as isoaffineyin (5,7,4,3′,5′-pentahydroxyflavone-6-C-glucoside, 15) from
Manikara indica (family: Sapotaceae), the flavonoid candidate exerted promising inhibition against porcine lens aldose reductase activity with an IC50 value of 4.6 μM (epalrestat was used as positive control, IC50 = 0.87 μM).
The genistein derivatives (16-19) isolated from an EtOAc-soluble partition of the MeOH extract of a branch of Tetracera scandens (family:
Dilleniaceae) were evaluated to possess promising activities on Type-2 diabetes mellitus treatment since the test compounds significantly stimulated the uptake of glucose, adenosine monophosphate-activated kinase (AMPK), glucose transport protein-4 (GLUT4) and GLUT1 mRNA expressions and protein tyrosine phosphatase 1B (PTP1B) inhibition in L6 myotubes [51].
The IC50 values for isofavonoids 16-19 in inhibiting PTP1B activities were
determined as 31.75 ± 0.27, 28.13 ± 0.19, 20.63 ± 0.17 and 37.52 ± 0.31 μM,
respectively (ursolic acid was used as positive control with IC50 value of 5.13 ± 0.45μM). No muscle cell toxicity was reported with compounds 17-19, while compound 16 reduced muscle cell viability with IC50 value of
18.69 ± 0.19 μM. The investigators, thus, demonstrated that the isoflavonoids constituents (16-19) of T. scandens stimulate glucose-uptake in basal and insulin-stimulated L6 myotubes in a dose-dependent manner - AMPK activation, GLUT4 and GLUT1 expressions and PTP1B inhibition by these bioactive constituents appeared to be involved in the mechanism of the stimulation of basal and insulin-responsive glucose-uptake. Hence, compounds 16-19 may be possible candidates of a novel therapeutic strategy
for Type-2 diabetes mellitus treatment, although further studies will be required to clarify the molecular mechanism of these bioactive constituents [51].
Isoorientin (20), isolated from the water and butanolic extracts of Cecropia obtusifolia (family: Ceropiaceae), exhibited potent hypoglycemic activity comparable to that of glibenclamide at a dose of 3 mg/kg body weight in diabetic rats [52].
Kim et al. [53] isolated a new flavonol glycoside, quercetin 3-O-α-L-arabinopyranosyl-(1Æ2)-β-D-glucopyranoside (21) along with the
known flavonoid glycosides such as kaempferol 3-O-β-D-glucopyranoside